Gene Linked With Kidney Disease In Blacks ID'd

WINSTON-SALEM, NC - Kidney disease is a growing public health problem, with approximately half a million individuals in the United States requiring dialysis treatments to replace the function of their failed kidneys. The problem is particularly acute among African-Americans, whose rates of kidney disease are four times higher than those of European Americans.

As reported online this month by the journal Science, collaborating research groups found that patients with focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) harbored variants in the APOL1 gene that changed the ApoL1 protein sequence. These variants are commonly found in individuals of recent African ancestry.

Furthermore, in a twist of evolutionary medicine, the disease-causing variants may have protected Africans against a lethal parasite, explaining why these genetic variants are so common in the population today.

Researchers at Wake Forest University Baptist Medical Center contributed to and participated in this scientific team, led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Universite Libre de Bruxelles. Together, they discovered a genetic explanation – with evolutionary roots – for the higher incidence of non-diabetic kidney disease in African-Americans.

“We found that the APOL1 risk genes for renal disease occur in more than 30 percent of African-American chromosomes,” explained co-senior author Martin Pollak, M.D., chief of nephrology at BIDMC and associate professor of medicine at Harvard Medical School. “In fact, the increased risk of kidney disease in individuals who inherited two copies of these variant forms of APOL1 is reported to be approximately 10-fold.”

FSGS is a form of injury to the kidney’s filtering system, which causes proteins to be lost into the urine and gradually reduces kidney function. ESKD, or end-stage kidney disease, is defined by kidney failure that has progressed to the point that the patient requires dialysis or kidney transplantation.

“It has long been thought that high blood pressure is a common cause of end stage kidney disease in African-Americans,” said study co-researcher Barry Freedman, M.D., John H. Felts III Professor and chief of the section on nephrology at WFUBMC. “However, the strong association between variants in the APOL1 gene and hypertension-attributed kidney disease suggested that this kidney disease truly resides in the spectrum of FSGS and is not due to hypertension as was initially believed.”

More than 2,000 study participants from the southeastern United States were recruited to the study by WFUBMC.

Last year, Freedman led a team of WFUBMC researchers who found that genetic variation near the MYH9 gene on chromosome 22 was also associated with increased risk of hypertension-attributed kidney disease in African-Americans. However, because genome analyses had shown a strong signal of natural selection in the region containing both the MYH9 and APOL1 genes, the authors reasoned that the location of the disease-causing genetic variants was in a broader region. They also predicted that the frequency of these variants would be markedly different between European-Americans and Africans.

Using data from the 1000 Genomes Project DNA data bank, the authors identified candidate genetic variants and tested for their presence in DNA sample sets. They found that two APOL1 variants – dubbed G1 and G2 – were associated with an increased risk of both FSGS and hypertension-attributed ESKD in African-Americans.

“G1 and G2 both changed the coding sequence of APOL1,” Pollak explained. “Further analyses revealed that these very same genetic variants [G1 and G2] conferred human immunity against the parasite responsible for sleeping sickness.”

African sleeping sickness is caused by an African trypanosome parasite, which is transmitted by the tsetse fly. The disease, which produces severe nervous system disorders that can ultimately lead to brain damage, coma and death, is estimated to affect tens of thousands of people, but is not found outside of Africa.

The APOL1 protein circulates in the blood and helps defend against trypanosomes, a finding initially discovered by co-senior author Etienne Pays, Ph.D., of the Universite Libre de Bruxelles, in Belgium. In the current study, Pays’ laboratory found that the plasma from patients harboring the G1 and G2 variants inactivated the trypanosomes that cause the deadliest forms of African Sleeping Sickness, as did the APOL1 protein with these same variants inserted.

“We were excited that our findings appeared to relate kidney disease in the United States with human evolution and parasite infection in Africa,” Pollak said. “While there are many details that remain to be clarified in future studies, we do know that sickle-cell disease is a well-established precedent for this model, in which one copy of the mutation confers protection against a parasitic infection but two copies of the mutation can cause severe disease.” Pollak explained that, when present in a single copy, certain hemoglobin mutations protect against malaria. But two copies cause sickle cell disease or thalassemia, severe red-blood cell diseases.

“It appears that we may have found a similar situation in APOL1,” Pollack added. “Consequently, while these genetic variants protect against sleeping sickness, they also greatly increase a person’s susceptibility to kidney disease. We hope that these new findings will not only lead us to a better understanding of the underlying mechanisms leading to kidney failure, but will also help us develop new ways to treat trypanosome infection and kidney disease.”

This study was supported, in part, by grants from the National Institutes of Health, the National Institute of Diabetes, Digestive and Kidney Disease (NIDDK) Intramural Research Program; the Intramural Research Program of the National Cancer Institute, Center for Cancer Research; the NephCure Foundation; the CIBLES Program of the Walloon Region; and the Fonds National de la Recherche Scientifique and the Interuniversity Attraction Poles Prgoram of the Belgian Science Policy.

In addition to Pollak, Pays and Freedman, coauthors include Donald Bowden, Carl Langefeld, and Pamela Hicks of Wake Forest University Baptist Medical Center; Giulio Genovese and David Friedman (co-first authors) and Andrea Bernhardy of BIDMC’s Department of Nephrology; Michael Ross and Andrea Uscinski Knob of Brigham and Women’s Hospital, Boston; Laurence Lecordier, Pierrick Uzureau and Benoit Vanhollebeke of Universite Libre de Bruxelles, Belgium; Taras Oleksyk of the University of Puerto Rico at Mayaguez; Cheryl Winkler of NCI-Frederick, Maryland; and Jeffrey Kopp of the NIDDK.Wake Forest University Baptist Medical Center (www.wfubmc.edu) is an academic health system comprised of Wake Forest University Health Sciences, which operates the university’s School of Medicine, Wake Forest University Physicians and North Carolina Baptist Hospital. U.S. News & World Report ranks the School of Medicine among the nation's best medical and osteopathic schools: 33rd in primary care, 44th in research, 23rd for its physician assistant program, and 11th for its joint program with the UNC-Greensboro to train nurse anesthetists. Best Doctors in America includes 214 of the Wake Forest medical school faculty. The institution is in the top third in funding by the National Institutes of Health and fourth in the Southeast in revenues from its licensed intellectual property. The Medical Center has been ranked as one of “America’s Best Hospitals” by U.S. News & World Report since 1993.